Advancing therapeutics against novel targets for CNS diseases using the NETSseq platform

Developing drugs to target disorders of the central nervous system (CNS) offers significant opportunities for the pharmaceutical industry, with an aging population becoming increasingly susceptible to neurodegenerative disorders.

However, identifying drug targets in this area is particularly difficult, a challenge that Cerevance – a biotech company based in Boston, MA, USA and Cambridge, UK – is looking to address.

Cerevance has developed proprietary technology, named NETSseq, that can comprehensively profile specific brain cell types, allowing for comparisons between healthy and diseased brain tissue.

Challenges in CNS drug discovery

The complexity of the brain makes it very difficult to study, with hundreds of different cell types wired into intricate pathways. Identifying protein targets is challenging, as many are expressed across different brain cell types, and so targeting them could result in dangerous ‘on-target’ side-effects.

An ideal target protein is therefore produced selectively in cell types that are relevant to the disease. This requires an understanding of which proteins are made by which brain cells, and which ones are disrupted in the disorder.

Animal models of human CNS diseases are generally based on rare familial forms, making them less than ideal for modeling disease mechanisms. Furthermore, although there are similarities between animal and human brain structures, even highly conserved regions show species differences, making results from animal models hard to extrapolate to humans.

The analysis of human tissues, therefore, provides better insights into the underlying changes in disease-associated brain tissues.

Cerevance has collected over 9,000 healthy and diseased tissue samples from 21 brain bank partners. This collection corresponds to over 50 different brain regions and represents a range of diseases including Parkinson’s, Alzheimer’s and Huntingdon’s.

The company is using these samples, alongside its proprietary NETSseq platform, to identify novel therapeutic targets, looking for proteins expressed highly selectively in brain cell types that either die in, play a key role in, or are disrupted by disease.

The NETSseq platform

The NETSseq approach was invented by Dr. Nat Heintz and Dr. Xiao Xu at Rockefeller University. It enables comprehensive profiling of specific brain cell types – including both neurons and glial cells – in mature human brain tissue.

The approach involves using antibodies against nuclear proteins, endoplasmic reticulum proteins and membrane proteins, as well as RNA probes against any cell-type-specific transcripts.

These probes tag specific cell types in brain tissue, so their nuclei can be sorted by FACS. Defined sub-populations then undergo RNA extraction and sequencing, and the cell-type-specific transcriptomes are analyzed to identify potential targets of interest.

Production of a cell type specific transcriptome using the NETSseq platform

Figure 1. Production of a cell-type-specific transcriptome using the NETSseq platform. Image Credit: Tecan

Industrialization of the NETSseq platform

Cerevance has optimized the NETSseq process to be performed on an industrial scale.

The company’s first challenge was the handling of post mortem material, and particularly the need to fix nuclei, as this can severely degrade RNA, leading to low quality and yields. Fortunately, the Trio RNA-Seq™ library preparation kit (Tecan) results in reproducible amplification from these challenging templates, producing good quality libraries from precious brain material.

The NETSseq process is carried out in two stages. The first stage is performed in a ‘clean room’ and involves RNA extraction and pre-amplification. The samples are then transferred to a ‘dirty room’ for post-amplification activities on a DreamPrep™ NGS workstation (Tecan). This platform offers a complete walk-away workflow, with an integrated plate reader and PCR thermal cycler to fully automate library amplification, quantification and pooling.

Automation of the workflow has enabled the company to increase throughput and avoid contamination, transforming processing from a single 96-well plate a week to at least four full plates.

Advantages of NETSseq

NETSseq enables Cerevance to measure the expression of significantly more genes than single-cell or single-nuclei analysis, including genes expressed at lower levels.

This more sensitive approach is critical for the discovery of molecular signatures of late-onset degenerative diseases, and for the identification of potential therapeutic targets – cell surface receptors, enzymes, etc. – that may be expressed at low levels in the mature brain.

Applications and future plans

Cerevance is using NETSseq to assemble a large and detailed CNS transcriptome database from rare clinical samples. So far, it has produced more than 5,000 high-quality transcriptomes – including for Parkinson’s and Alzheimer’s – and this is rapidly expanding into other areas.

In total, 72 cell types have been fully validated with additional cell types ongoing, and the NETSseq approach has resulted in 10 novel targets entering drug discovery, with the most advanced target resulting in a candidate molecule now in Phase II clinical trials for Parkinson’s disease.

More information on the NETSseq platform can be found in Steven’s talk at the Tecan Genomics Symposium - here.

About Tecan

​Tecan is a leading global provider of automated laboratory instruments and solutions. Its systems and components help people working in clinical diagnostics, basic and translational research and drug discovery bring their science to life.

In particular, the company develops, produces, markets and supports automated workflow solutions that empower laboratories to achieve more. Its Cavro branded instrument components are chosen by leading instrumentation suppliers across multiple disciplines.

Tecan works side by side with a range of clients, including diagnostic laboratories, pharmaceutical and biotechnology companies and university research centers. Its expertise extends to developing and manufacturing OEM instruments and components, marketed by its partner companies. Whatever the project – large or small, simple or complex – helping its clients to achieve their goals comes first.

The company holds a leading position in all the sectors it works in, and has changed the way things are done in research and development labs around the world. In diagnostics, for instance, it has raised the bar when it comes to the reproducibility and throughput of testing.

In under four decades, Tecan has grown from a Swiss family business to a brand that is well established on the global stage of life sciences. From pioneering days on a farm to the leading role the business assumes today, Tecan empowers research, diagnostics and many applied markets around the world.

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Last updated: Mar 28, 2022 at 3:21 AM


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